This invention is in the field of chemical restructuring of methotrexate and related pharmaceutical agents known to have poor bioavailability, cause toxicity or adverse drug reactions in noncancerous tissues as a side effect, by producing their orotate derivatives. More particularly, it concerns derivatives of the folate antagonists, methotrexate, trimetrexate and raltitrexed that are used as anticancer drugs on in non-malignant disorders characterized by rapid cellular growth.
In the 58 years since Farber first described clinical remissions after use of the folate antagonist aminopterin for children with acute leukemia, methotrexate has been used to treat millions of patients with both malignant and autoimmune diseases. Methotrexate is now the most widely prescribed disease-modifying antirheumatic drug (DMARD), used by at least 500,000 patients worldwide with rheumatoid arthritis. Methotrexate is prescribed for more patients with rheumatoid arthritis than all of the biologic drugs in current use combined. It is the most commonly reported agent used in combination with other DMARDs where clear additive therapeutic value is demonstrated. Low doses of methotrexate administered orally, have been iused in treatment of multiple sclerosis with minimal toxicity. However, when administered orally the serum level of methotrexate is not sufficient because of poor oral bioavailability. The fear of severe organ-associated toxicity has led to development of guidelines for monitoring liver toxicity which has so frightened physicians and limited its earlier use. In addition, the recognition that methotrexate-associated pulmonary disease is most often a subacute syndrome associated with dry cough, often with dyspnea and fever, has led to earlier recognition and avoidance of permanent lung sequelae in many patients receiving the drug. The realization that many of the gastrointenstinal, bone marrow and other toxicities, which so frequently limited its use prior to 1980s could be avoided by the use of folate supplementation has also given both clinicians and patients a measure of security when prescribing this potent antimetabolite.
However, the overall sophistication regarding the many issues and complexities associated with the use of methotrexate is still somewhat low. Many clinicians use folic acid, while others use methotrexate with a variety of other drugs in patients who may be at increased risk of adverse events due to drug interactions. Ideas and prescribing patterns associated with maximum weekly doses, use in the elderly, monitoring of blood tests, and when to “give up” and add other agents to be prescribed with methotrexate are often followed without specific rigorous scientific support.
The Food and Drug Administration approved low-dose methotrexate use in treatment of psoriasis in 1960 and in the treatment of rheumatoid arthritis in 1988. Currently, methotrexate is prescribed by rheumatologists world-wide and has proved to be a very effective, fast-working, second-line antirheumatic agent with the best efficacy-toxicity ratio. Nevertheless, the main reason for discontinuation of methotrexate is not inefficacy but toxicity. Because of its clear-cut and long-lasting efficacy, much effort is currently being made to develop strategies to decrease or prevent its toxicity. In approximately 30% of rheumatoid arthritis patients, toxicity leads to discontinuation of methotrexate therapy. Therefore, the present invention provides two solutions to diminishing the toxicity of methotrexate: 1) by improving the bioavailability of methotrexate and therefore reducing the effective dose of methotrexate, and 2) by improving the clearance rate of methotrexate.
Side Effects—The side effects of methotrexate are quite common. The severity varies, but most side effects are mild, reversible, and can be treated conservatively. Side effects like nausea, changes in transaminases, and somatitis are often encountered and are dose dependent; others like pneumonitis and hepatocellular changes are not. However, on 30% of patients with rheumatoid arthirits, toxicity leads to discontinuation of methotrexate therapy within one year. Only a few determinants for toxicity are known, such as increasing age and poor renal function. Another important problem is that although the risk of side effects may be slightly higher in the first six months, the risk for all sorts of adverse effects is permanent, implying a need for long-term monitoring. At least part of the side effects of methotrexate seems to be directly related to its folate antagonism and its cytostatic effects especially in tissues with high turnover. Methotrexate is prescribed in a dose of 5 mg/week to 15 mg/week and the maximum dose is 25 to 30 mg/week. Reduced bioavailability of methotrexate accounts for these effects. Therefore, the present invention provides strategies to improve the bioavailability of methotrexate by converting it to an orotate form and thus reduce its toxicity.
Because of the value of methotrexate in therapy, many investigators have modified the structure of methotrexate in attempts to synthesize more potent derivatives. U.S. Pat. No. 5,698,556, issued to Carcy L. Chan, and U.S. Pat. No. 5,958,928, issued to Masahiko Mihara. Methotrexate enters cells via the reduced folate carrier which also transports the naturally occurring reduced folates. Efflux of methotrexate occurs through mechanisms that are somewhat different from influx and are energy-dependent. Multi-drug resistance-associated proteins have been identified which transport methotrexate, folic acid and 5-CHO—FH4 out of cells. Inhibition of the multi drug resistance proteins results in significant accumulation of intracellular methotrexate. The present invention provides strategies to improve the efflux and clearance of methotrexate by converting it to an orotate form and improving its clearance. More effective and less toxic agents are widely sought and are a fundamental object of the invention. The pertinent subject matter of the above references is specifically incorporated herein by reference.